Reduced glucose metabolism always accompanies Alzheimer's disease (AD) and the decline is highly correlated with the decline in cognition. Promotion of AD pathology by manipulation of glucose/oxygen utilization in pre-clinical models supports the possibility that these deficits are not mere consequences of the disease, but promote the disease and are potential therapeutic targets. An understanding of the underlying basis for the decline in glucose utilization and its consequences are required to therapeutically target glucose utilization. The decline in mental function before AD patients die is highly correlated to changes in the activities of enzymes related to the mitochondrial tricarboxylic acid (TCA) cycle including the entry level enzyme- the pyruvate dehydrogenase complex (PDHC) and the rate controlling step-?-ketoglutrate dehydrogenase (KGDHC. The proposed studies will test the overall hypothesis that the changes in the TCA cycle underlie the abnormal metabolism and pathology in AD and that reversing them or the downstream consequences will benefit AD patients. We propose that determining the post-translational modifications that diminish the activity of KGDHC in brains from AD patients will reveal the cause of the modification and suggest effective ways to reverse the deficit. The possibility that KGDHC and PDHC may directly modify other TCA cycle enzymes will be tested. The experiments will test whether diminished KGDHC alters the response to drugs that promote mitogenesis and determine the link between the KGDHC and signals for mitochondrial repair in order to manipulate them to enhance mitochondrial repair. Surprisingly little is known about the response of the genes and proteins of the entire TCA cycle to metabolic perturbations and some ?mitogenic? therapies may diminish activities. Thus, the proposal is to test the response of these enzymes at the level of the gene, activity and protein (including post-translational modifications by acetyl or succinyl groups) to select metabolic perturbations to determine better therapeutic targets. The experiments will test the hypothesis that changes in the mitochondrial TCA cycle and the consequent downstream signaling changes are central to the disease process and provide a therapeutic target that is not responsive to mitogenic therapies. Successful completion of these studies will identify additional mechanisms to reverse the deficits and ameliorate the disease process.